The amidoalkylation of aromatic hydrocarbons

The Nyberg procedure (the use of trifluoroacetic acid in chloroform) for the efficient amidoalkylation of aromatic hydrocarbons is limited to substrates more nucleophilic than benzene. The reaction involves protonation of the electrophile, cleavage to a carbonium ion and alkylation of the nucleophile by the carbonium ion. Either the cleavage step or the alkylation step may be rate-determining. The present work identifies some cases where a carbonium ion is formed but fails to alkylate the nucleophile (with benzene and nitro-substituted benzenes as nucleophiles) and other cases where the reaction conditions are not sufficient to permit cleavage of the protonated electrophile (the reactions of N-phthalimidomethylamides).     

Kinetics of hydrolysis of 8-(arylamino)-2'-deoxyguanosines

The 8-(arylamino)-2'-deoxyguanosines, or C-8 adducts, are the major adducts formed by reaction of N-arylnitrenium ions derived from carcinogenic and mutagenic amines with 2'-deoxyguanosine (d-G) and guanosine residues of DNA. The hydrolysis kinetics of three C-8 adducts 1a-c were determined by UV and HPLC methods at 20 degrees C under acidic, neutral, and mildly alkaline conditions. At pH < 2 the dominant hydrolysis process is spontaneous cleavage of the C-N bond of the doubly protonated substrate, 1H(2)(+2) (Scheme 2). The C-8 adducts are 2- to 5-fold more reactive than d-G under these conditions. At 3 < pH < 6 the hydrolysis kinetics are dominated by cleavage of the C-N bond of the monoprotonated nucleoside 1H(+). Under these conditions the hydrolysis kinetics are accelerated by 40- to 1300-fold over that of d-G. The rate increase appears to be caused by a combination of steric acceleration of C-N bond cleavage and a decrease in the ionization constant of 1H(+), K(a1), due to the electron-donating properties of the arylamino C-8 substituent. Under neutral pH conditions a slow (k(obs) approximately 10(-8) s(-1) to 5 x 10(-7) s(-1)) spontaneous cleavage of the C-N bond of the neutral nucleoside, 1, occurs that has not been previously reported for simple purine nucleosides. Finally, under mildly alkaline conditions a process consistent with spontaneous decomposition of the anion 1(-) or OH(-)-induced decomposition of 1 is observed. The latter process has been observed for other purine nucleosides, including the closely related 1d, and involves nucleophilic attack of OH(-) on C-8 to cleave the imidazole ring of the purine.     

Chemical ionization of ethylene dibromide with ammonia gas

Under ammonia chemical ionization conditions, a fragment ion of ethylene dibromide undergoes a nucleophilic substitution reaction which is demostrated to be highly pressure-dependent upon the reagent gas concentration. This reaction is strongly influenced by the stability of the intermediate carbonium ion and the ability of the substituted product ion to be stabilized by intramolecular hydrogen bonding.     

Purine N-oxides—XL The 3-acyloxypurine 8-substitution reaction: Scope: Syntheses of 8-substituted xanthines and guanines

The 3-acyloxypurine 8-substitution reaction is a substitution-elimination reaction involving attack at C-8 by inorganic or organic nucleophiles and departure of an acyloxy group from N-3. It has been studied with 3-acetoxyxanthine, 3-hydroxyguanine and a number of related derivatives and is the method of choice for the preparation of many 8-substituted xanthines or guanines. It proceeds extremely rapidly in neutral aqueous solutions at room temperature. With water alone an 8-hydroxypurine results, and water always competes to some degree with other nucleophiles. The reaction can be carried out in dipolar aprotic solvents, in which it is also possible to prepare the acyloxy derivative in situ and to choose more effective leaving groups such as mesyloxy or tosyloxy. The reaction has been demonstrated with chloride, bromide, nitrite, and azide ions; with the thioether of methionine; a variety of pyridine derivatives, and with primary and secondary alcohols. This reaction is apparently restricted to 3-acyloxypurines which are also substituted at position-2. The behaviour of 3-acetoxy-1-methylxanthine is similar to that of 3-acetoxyxanthine, but 3-acetoxy-7-methylxanthine fails to undergo the reaction.     

Kinetics and mechanisms of the catalytic reactions of formaldehyde with copper oxides and a copper ion complex in aqueous alkali

The kinetics of the autocatalytic reactions of formaldehyde with copper(II) and copper(I) oxides and with the Cu²⁺ ion of the copper EDTA complex, as well as formaldehyde disproportionation in the presence of copper metal, have been investigated in aqueous solutions of sodium hydroxide. Two likely reaction mechanisms are presented. The difference between these mechanisms does not alter the observed kinetics of the processes, whose rate is determined by their first, slow step, namely, the oxidation of the methylene glycol anion adsorbed on the copper surface into formic acid. In the slow step of the first mechanism, a hydride ion is abstracted from the methylene glycol anion and is transferred to copper. In the slow step of the second mechanism, the methylene glycol anion undergoes anodic oxidation, releasing a hydrogen atom and an electron. In the rapid steps of the first mechanism, the hydride ion undergoes anodic oxidation to hydrogen, the copper compound undergoes cathodic reduction to copper metal, and, simultaneously, the electron and hydrogen are transferred to a nonionized formaldehyde molecule to yield methanol. Mathematical models are suggested for the reactions. The effective rate constants and activation energies of the slow steps of the reactions have been determined. The effective rate constants of the noncatalytic reduction reactions of the copper compounds and the ratios of the rates of the rapid hydrogen and methanol formation reactions have been estimated.     

Nucleoside synthesis from 3-alkylated sugars: role of 3beta-oxy substituents in directing nucleoside formation

Using Vorbrüggen's protocol, reaction of persilylated uracil with xylofuranose derivatives having 3beta-oxy-3alpha-alkyl substitution produced both alpha- and beta-nucleosides. Only the beta-nucleosides were formed from substrates having the reverse stereochemistry at C-3 or lacking the 3-alkyl substituent. Participation of the 3beta-oxy substituent in stabilizing the incipient C-1 carbonium ion (or oxonium ion) intermediate has been suggested from analysis of energy-minimized conformations.     

Gas phase glycosidic cleavage of oxynions from alkyl glycosides

The oxyanion [M? H]^? from several methylglycosides were generated by fast atom bombardment and their decomposition was studied by mass-analysed ion kinetic energy spectrometry. The main decomposition pathway is the loss of methanol. The hydroxylic hydrogen arises by proton transfer from the hydroxyl groups of the sugar. In the gluco-series, no anomeric effect is found. The absence of either the hydroxyl groups at C-2 or C-6 does not inhibit the glycosidic cleavage. However, the blocking of both the hydroxyl groups at C-4 and C-6, by a benzylidene group or two methyl groups, inhibit completely the glycosidic cleavage. From these results, it is proposed that the glycosidic cleavage occurs after opening the sugar ring by a vicinal attack of an oxyanion at C-6 or C-4 to the C-5 carbon atom. Then, the ionized hemi-acetals fragment into a methanolate anion and a 5,6- or 4,5-anhydrosugar which exchange another proton before their separation into charged and neutral species.     

Lead(IV) acetate oxidative ring-opening of 2,3-epoxy primary alcohols: a new entry to optically active α-hydroxy carbonyl compounds

The treatment of 2,3-epoxy primary alcohols with lead(IV) acetate (LTA) leads to α-acetoxy aldehydes or α-acetoxy ketones, through the nucleophilic ring-opening of an intermediate oxonium and the subsequent carbon-carbon bond cleavage. This reaction represents a new route to optically active α-hydroxy carbonyl compounds.     

Fragmentation of conjugate bases of esters derived from multifunctional alcohols including triacylglycerols

Enolate anions of esters from 1,2 and 1,3 diols undergo an internal nucleophilic substitution reaction that produces a β-ketoester and an alkoxide ion within the molecular species. These intermediate ions undergo two competitive fragmentation pathways. The first pathway corresponds to a second nucleophilic substitution of the ketoester by the alkoxide that yields a neutral cyclic ether and the β-ketoacid carboxylate. The latter then loses carbon dioxide and produces the enolate anion of the corresponding ketone. The second proposed pathway is stepwise: it starts with a proton transfer from the methylene group between the two carbonyls to the alkoxide anion that produces an alcohol and the enolate ion of the β-ketoester inside the molecular species. The latter undergoes cleavage of the ester bond induced by the negative charge to yield an ion-dipole complex composed of a neutral acylketene and an alkoxide ion. The direct dissociation of this ion-dipole complex competes with an internal proton exchange to yield a new complex that consists of an alcohol molecule and the anion of the acylketene, which can also dissociate. The fragmentation pathway that leads to the ketone enolate is sensitive to the relative positions (1,2 or 1,3) of the esters on the molecular backbone. This position-sensitive reaction is useful for the assignment of the primary and secondary positions in triacylglycerols, even in mixtures, as shown by some examples.     

A computational study of remote C-H activation by amine radical cations: implications for the photochemical reduction of carbon dioxide

A computational study, using density functional theory calibrated against higher-level methods, has been undertaken to evaluate tertiary amines whose radical cations might lose hydrogen atoms from positions other than the alpha carbons. The purpose was to find photochemically activated reducing agents for carbon dioxide that could be regenerated in a separate photochemical reaction. The calculations have revealed two reactions that might be suitable for this purpose. In one, the nitrogen of the radical cation makes a bond to a remote carbon with simultaneous displacement of a hydrogen atom. In the other, a remote hydrogen atom is transferred to the nitrogen, thereby creating a distonic radical cation that can lose a hydrogen atom beta to the radical site. The latter reaction is found to be particularly favorable since it apparently involves a surface crossing that allows the amine radical cation and CO2 radical anion to transform smoothly to a ground-state formate ion and an alkene. A number of structural motifs are investigated for the amines. The lower ionization potential of aromatic amines, compared to their aliphatic analogues, is desirable in that it could permit the use of longer wavelength light to drive the reaction. However, a thermochemical cycle shows that the reduction in ionization potential must be matched by an increase in proton affinity of the amine if the intramolecular hydrogen transfer is to be exothermic. Most aromatic amines do not satisfy this criterion and, hence, would have to rely on the displacement reaction for hydrogen-atom release if they were to be used as renewable reagents for CO2 reduction. Examples of specific aromatic and aliphatic tertiary amines that should be suitable for the purpose are presented, and their relative merits and weaknesses are discussed.     

Kinetic and thermodynamic barriers to carbon and oxygen alkylation of phenol and phenoxide ion by the 1-(4-methoxyphenyl)ethyl carbocation

Rate constant ratios for addition of the three nucleophilic sites of phenol to the 1-(4-methoxyphenyl)ethyl carbocation (1+) in 50/50 (v/v) trifluoroethanol/water were determined from the relative yields of the three phenol adducts, and absolute rate constants were determined from product rate constant ratios for addition of phenol and azide ion to 1+ using k(az) = 5 x 10(9) M(-1) s(-1) for the diffusion-limited reaction of azide ion. A selectivity of 230:20:1 was determined for alkylation of phenol at oxygen, C-4 and C-2 to form 1-OPh and biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH), respectively, and of 2:2:1 for alkylation of the corresponding nucleophilic sites of phenoxide ion in diffusion-limited reactions. The Mayr nucleophilicity parameter for C-4 of phenol is N = 2.0. Encounter-limited addition of phenoxide ion to 1+ to form 1-OPh is faster than encounter-limited addition of oxygen anions that are either more or less basic than phenoxide ion. Only the products of solvolysis are observed from acid-catalyzed cleavage of 1-OPh in 50/50 (v/v) trifluoroethanol/water, but a 50% yield of biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH) are observed from spontaneous cleavage of 1-OPh, where the leaving group is phenoxide ion, because of the very low kinetic barriers to collapse of the ion pair intermediate 1+.PhO-. The 230-fold larger rate constant for O-compared to C-2-alkylation of phenol is due primarily to the larger thermodynamic driving force for oxygen addition. There are similar Marcus intrinsic barriers for these two reactions.     

Electronically Mediated Selectivity in Ring Opening of 1-Azirines. The 3-X Mode: Convenient Route to 3-Oxazolines

The mild base-promoted reaction of methyl 2-phenyl-1-azirine-3-acetate (1) with aldehydes and acetone provides a new and simple route to the 3-oxazolines 5, which are formed in good yields by the electrophilic trapping of an imino anion produced by C-N bond cleavage in the 1-azirine enolate intermediate 6. Chloranil oxidation of 5 containing an aromatic substituent at C-2 affords oxazoles 7, while reaction of 5 containing an aliphatic group at C-2 produces 5-methylene-3-oxazolines 8 and 5-spiro-2-oxazolines 9 in addition to 7.     

A unique autocatalytic process and evidence for a concerted-stepwise mechanism transition in the dissociative electron-transfer reduction of aryl thiocyanates

Electrochemical reduction of p-methyl-, p-methoxy-, and 3,5-dinitrophenyl thiocyanates as well as p-methyl- and p-methoxyphenyl disulfides was investigated in acetonitrile at an inert electrode. This series of compounds reveals a striking change in the reductive cleavage mechanism of the S-CN bond in thiocyanates as a function of the substituent on the aryl ring of the aryl thiocyanate. With nitro substituents, a stepwise mechanism, with an anion radical as the intermediate, takes place. When electron-donating groups (methyl and methoxy) are present, voltammetric as well as convolution analyses provide clear evidence for a transition between the concerted and stepwise mechanisms based on the magnitude of the transfer coefficient alpha. Moreover, a very interesting autocatalytic process is involved during the electrochemical reduction of these compounds. This process involves a nucleophilic substitution reaction on the initial aryl thiocyanate by the electrochemically generated arenethiolate ion. As a result of this unusual process, the electrochemical characteristics (peak potential and peak width) of the investigated series are concentration dependent.     

Rearrangement, nucleophilic substitution, and halogen switch reactions of alkyl halides over NaY Zeolite: formation of the bicyclobutonium cation inside the zeolite cavity

Rearrangement and nucleophilic substitution of cyclopropylcarbinyl bromide over NaY and NaY impregnated with NaCl was observed at room temperature. The first-order kinetics are consistent with ionization to the bicyclobutonium cation, followed by internal return of the bromide anion or nucleophilic attack by impregnated NaCl to form cyclopropylcarbinyl, cyclobutyl, and allylcarbinyl chlorides. The product distribution analysis revealed that neither a purely kinetic distribution, similar to what is found in solution, nor the thermodynamic ratio, which favors the allylcarbinyl halide, was observed. Calculations showed that bicyclobutonium and cyclopropylcarbinyl carbocations are minimal over the zeolite structure, and stabilized by hydrogen bonding with the framework structure. A new process of nucleophilic substitution is reported, namely halogen switch, involving alkyl chlorides and bromides of different structures. The reaction occurs inside the zeolite pores, due to the confinement effects and is an additional proof of carbocation formation on zeolites. The results support the idea that zeolites act as solid solvents, permitting ionization and solvation of ionic species.     

35 GHz ENDOR characterization of the "very rapid" signal of xanthine oxidase reacted with 2-hydroxy-6-methylpurine (13C8): evidence against direct Mo-C8 interaction.

Xanthine oxidase is a molybdenum-containing enzyme that catalyzes the hydroxylation of xanthine and a wide variety of other aromatic heterocycles. In the course of the reaction with xanthine and substrates such as 2-hydroxy-6-methylpurine (HMP), the enzyme gives rise to a Mo(V) EPR signal, denoted "very rapid", that arises from an authentic catalytic intermediate. The two alternative catalytic mechanisms proposed for this enzyme differ critically in whether the distance between Mo and C8 of the purine nucleus in this intermediate is short enough to admit a direct bonding interaction. To examine this distance, we have performed 13C ENDOR measurements of the "very rapid" EPR signal generated by xanthine oxidase during reaction with 13C8-HMP. The resulting (13)C8 hyperfine tensor, A = [10.2(1), 7.0(1), 6.5(1)] MHz, is discussed in the framework of a detailed consideration of factors involved in extracting metrical parameters from an anisotropic hyperfine interaction composed of contributions from multiple sources, in particular, the effect of the local contributions from spin density on (13)C8. The analysis presented here gives a Mo...C distance whose value is expected to be ca. 2.7-2.9 A in the "very rapid" intermediates formed with both xanthine and HMP, consistent with plausible bond lengths for a Mo-O-C8 fragment where C8 is a trigonal-planar aromatic carbon. The difference from earlier conclusions is explained. The data thus do not support the existence of a direct Mo-C bond in the signal-giving species. This conclusion supports a mechanism that does not involve such an interaction and which begins with base-assisted nucleophilic attack of the Mo(VI)-OH group on the C-8 of substrate, with concomitant hydride transfer to the Mo=S group to give Mo(IV)-SH; the EPR-active "very rapid" species then forms by one-electron oxidation and deprotonation to yield the EPR-detectable Mo(V)OS(OR) species. We further discuss the complexities and limitations of the semiempirical method used to arrive at these conclusions.     

The redox behavior of gem-dihalo compounds: 9,9-dibromofluorene, 9,9-dichlorofluorene and dichlorodiphenylmethane

The redox behavior of several gem-dihalo compounds has been examined at platinum and vitreous carbon electrodes in dimethylformamide. The reduction of 9,9-dichlorofluorene is initially an overall two-electron process which involves cleavage of chloride ion and the formation of 9-chlorofluorenyl anion. The final products and their distribution are then dependent upon the relative rates of reduction of the parent compound, nucleophilic attack of 9-chlorofluorenyl anion on the parent compound, and proton availability. If reaction by substitution is permitted to predominate, 9,9′-dichlorobifluorenyl results. This species is electroactive at the applied potential and undergoes reductive dechlorination to give bifluorenylidene. In contrast, if either the rate of reduction of 9,9-dichlorofluorene of the rate of protonation of 9-chlorofluorenyl anion exceeds the rate of substitution, the predominant product becomes 9-chlorofluorene. Reduction of this species then gives a mixture of fluorene and bifluorenyl when electrolysis is effected in an aprotic medium and fluorene when electrolysis is performed in the presence of diethyl malonate, a weak proton donor. Dichlorodiphenylmethane and 9,9-dibromofluorene also undergo reductive dehalogenation to give monomeric and dimeric products by pathways analogous to those observed for dichlorofluorene. In the case of dibromofluorene, however, the product distribution is also potential dependent since the intermediate 9-bromofluorenyl radical may not be reduced at the applied potential. No evidence was obtained in these studies to support previous claims of carbenes and/or carbene radical anions in these reductions.     

Deconvoluting the memory effect in Pd-catalyzed allylic alkylation: Effect of leaving group and added chloride

An analysis of product distributions in the Tsuji-Trost reaction indicates that several instances of reported "memory effects" can be attributed to slow interconversion of the initially formed syn- and anti-[Pd(eta3-allyl)] complexes. Addition of chloride triggers a true memory effect, in which the allylic terminus originally bearing the leaving group has a higher reactivity. The latter effect, termed regioretention, can be rationalized by ionization from a palladium complex bearing a chloride ion, forming an unsymmetrically substituted [Pd(eta3-allyl)] complex. DFT calculations verify that the position trans to the phosphine ligand is more reactive both in the initial ionization and in the subsequent nucleophilic attack.     

Hydrogen migrations in mass spectrometry. V—loss of olefin from n-propyl esters following chemical ionization

The sources of the migrating hydrogen in the elimination of propylene from the protonated and ethylated n-propyl acetate and n-propyl benzoate molecules have been determined by studying the CH₄ and H₂ chemical ionization mass spectra of esters specifically deuterated in the propyl group. It is shown that the migrating hydrogen originates from C-1 ( ～ 27%), C-2 ( ～ 23%) and C-3 ( ～ 50%) of the propyl group, independent of ester and mode of ionization. It is argued that the observed reaction involves specific competing H-migration reactions from each propyl position to the ether oxygen in a keto-protonated (ethylated) ester molecule.     

The chemistry of 4-pyrimidinones: Acetylation and ring-opening reactions

4(3H)-Pyrimidinone, as well as its 5-acetoxy and 5-methoxy derivatives, undergoes selective acetylation at N-1 when treated with acetic anhydride. In the presence of water, these 1-acetylpyrimidines undergo spontaneous covalent hydration at C-2 and cleavage of the 1,2-bond to give crystalline cis-3-acetylamino-N-formyl-acrylamides, generally in good yield. In contrast, the 6-methyl derivative of 4(3H)-pyrimidinone forms an equilibrium mixture of acetylated products that undergo the ring opening process to only a very limited extent, the major product (11%) being the 3-formylamino-N-acetylacrylamide derivative formed via N-3 acetylation and cleavage of the 2,3-bond.     

Experimental and theoretical analyses of azulene synthesis from tropones and active methylene compounds: reaction of 2-methoxytropone and malononitrile

A representative azulene formation from an active troponoid precursor (2-methoxytropone) and an active methylene compound (malononitrile) has been analyzed both experimentally and theoretically. (2)H-Tracer experiments using 2-methoxy[3,5,7-(2)H(3)]tropone (2-d(3)) and malononitrile anion give 2-amino-1,3-dicyano[4,6,8-(2)H(3)]azulene (1-d(3)) in quantitative yield. New and stable (2)H-incorporated reaction intermediates have been isolated, and main intermediates have been detected by careful low-temperature NMR measurements. The detection has been guided by mechanistic considerations and B3LYP/6-31(+)G(d) calculations. The facile and quantitative one-pot formation of azulene 1 has been found to consist of a number of consecutive elementary processes: (a) The troponoid substrate, 2-methoxytropone (2), is subject to a nucleophilic substitution by the attack of malononitrile anion (HC(CN)(2)(-)) to form a Meisenheimer-type complex 3, which is rapidly converted to 2-troponylmalononitrile anion (5). (b) The anion 5 is converted to an isolable intermediate, 2-imino-2H-cyclohepta[b]furan-3-carbonitrile (6), by the first ring closure in the reaction. (c) A nucleophilic addition of the second HC(CN)(2)(-) toward the imine 6 at the C-8a position produces the second Meisenheimer-type adduct 7. (d) The second ring closure leads to 1-carbamoyl-1,3-dicyano-2-imino-2,3-dihydroazulene (11). A base attacks the imine 11, which results in generation of a conjugate base 12 of the final product, azulene 1.